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Table.  
Patient-Averaged Mean Cardiac Doses and Estimated Patient-Averaged Lifetime Excess Risks of Major Coronary Events Associated With Contemporary Breast Cancer Radiotherapy
Patient-Averaged Mean Cardiac Doses and Estimated Patient-Averaged Lifetime Excess Risks of Major Coronary Events Associated With Contemporary Breast Cancer Radiotherapy
1.
Little  MP, Azizova  TV, Bazyka  D,  et al.  Systematic review and meta-analysis of circulatory disease from exposure to low-level ionizing radiation and estimates of potential population mortality risks. Environ Health Perspect. 2012;120(11):1503-1511.
PubMedArticle
2.
Darby  SC, Ewertz  M, McGale  P,  et al.  Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987-998.
PubMedArticle
3.
Formenti  SC, DeWyngaert  JK, Jozsef  G, Goldberg  JD.  Prone vs supine positioning for breast cancer radiotherapy. JAMA. 2012;308(9):861-863.
PubMedArticle
4.
Ridker  PM, Buring  JE, Rifai  N, Cook  NR.  Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297(6):611-619.
PubMedArticle
5.
Chambless  LE, Heiss  G, Shahar  E, Earp  MJ, Toole  J.  Prediction of ischemic stroke risk in the Atherosclerosis Risk in Communities Study. Am J Epidemiol. 2004;160(3):259-269.
PubMedArticle
6.
Ng  J, Shuryak  I, Xu  Y, Clifford Chao  KS, Brenner  DJ, Burri  RJ.  Predicting the risk of secondary lung malignancies associated with whole-breast radiation therapy. Int J Radiat Oncol Biol Phys. 2012;83(4):1101-1106. Article
Research Letter
January 2014

Risk and Risk Reduction of Major Coronary Events Associated With Contemporary Breast Radiotherapy

Author Affiliations
  • 1Center for Radiological Research, Columbia University Medical Center, New York, New York
  • 2Department of Radiation Oncology, New York University School of Medicine, New York
JAMA Intern Med. 2014;174(1):158-160. doi:10.1001/jamainternmed.2013.11790

Long-term breast cancer survival rates have improved markedly over recent decades, so minimization of long-term treatment-related complications is increasingly important. Several reports have suggested links between breast cancer radiotherapy and long-term cardiovascular mortality.1 A recent analysis by Darby et al2 of patients treated with breast radiotherapy between 1958 and 2001 revealed a statistically significant linear dependence of the risk of major coronary events on mean cardiac dose. We use these historical data to estimate risks of major coronary events induced by modern breast radiotherapy. Our motivation is to quantify contemporary risks and also to guide efforts to minimize radiotherapy-induced cardiovascular risks.

Methods

The risk estimates derived here were based on contemporary patient-specific radiation doses averaged over the cardiac volume (hereafter, mean cardiac dose). These were derived from breast radiotherapy treatment plans for 48 patients with stage 0 through IIA breast cancer who were treated after 2005 at New York University Department of Radiation Oncology.3 Two treatment plans, for supine and for prone treatment positions, were generated for each patient. This was a prospective trial and received institutional review board approval. Informed consent was obtained from all participants.

Excess absolute risks (R) of radiotherapy-induced major coronary events (defined, as in Darby et al,2 as myocardial infarction, coronary revascularization, or death from ischemic heart disease) were calculated for each patient, on the basis of patient-specific mean cardiac doses and using the dose-response relationship reported by Darby et al for these end points:

R = 0.074 × D × B.

Here, D is the mean cardiac dose (in grays) and B is the baseline risk for a major coronary event, as defined in the previous paragraph. Because the radiation-associated risk depends on the baseline risk, we report risk estimates for typical low-risk, medium-risk, and high-risk patients, with baseline risks (B) estimated (Table) on the basis of the standard Reynolds algorithm.4 Cardiac risks were calculated over 20 years after radiotherapy, the approximate mean life expectancy after early-stage breast cancer.

Results

For standard supine-positioned radiotherapy, the patient-averaged mean cardiac dose was 1.37 (95% CI, 1.12-1.61) Gy (to convert to rad, multiply by 100), less than one-third of the average mean cardiac dose reported2 for breast radiotherapy from 1958 to 2001. As expected,3 mean cardiac doses were significantly lower for right-sided than for left-sided breast radiotherapy (2-tailed P = .001 for supine positioning and <.001 for prone positioning). For left-sided (but not right-sided) radiotherapy, treating in a prone position resulted in a halving of the mean cardiac dose.

Shown in the Table are the predicted lifetime risks of major coronary events induced by contemporary breast cancer radiotherapy, stratified by left vs right side radiotherapy, by supine vs prone treatment position, and by low, medium, or high baseline cardiac disease risk. The highest estimated radiotherapy-induced risks were for left-sided radiotherapy in high–cardiac risk women treated in the supine position (3.52% [95% CI, 1.47%-5.85%]), whereas the lowest risks were for right-sided radiotherapy in low–cardiac risk women (<0.1%).

Discussion

Cardiac doses from breast radiotherapy have generally decreased during recent decades (although not for all modern treatment techniques), so typical risks of major cardiac events associated with contemporary radiotherapy are lower than in earlier eras.2 Estimated lifetime risks of major coronary events for patients who receive radiotherapy for breast cancer are now in the range from 0.05% to 3.5%, with a typical value of 0.3% for a typical scenario. The highest cardiac doses and excess cardiac risks result from supine positioning during left-sided radiotherapy; for left-sided radiotherapy, prone positioning significantly reduces cardiac doses and risks.3 For right-sided radiotherapy, where the heart is always out of field, cardiac doses and risks are smaller, and prone vs supine positioning has little effect, although prone position radiotherapy does reduce ipsilateral lung doses and thus reduces potential second lung cancer risks.6

Because the effects of radiation exposure on cardiac disease risk seem to be multiplicative,2 the highest absolute radiation exposure risks correspond to the highest baseline cardiac risk. Consequently, radiotherapy-induced risks of major coronary events are likely to be reduced in these patients by targeting baseline cardiac risk factors (cholesterol, smoking, hypertension), by lifestyle modification, and/or by pharmacological treatment.

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Article Information

Corresponding Author: David J. Brenner, PhD, DSc, Center for Radiological Research, Columbia University Medical Center, 630 W 168th St, New York, NY 10032 (djb3@columbia.edu).

Published Online: October 28, 2013. doi:10.1001/jamainternmed.2013.11790.

Author Contributions: Drs Brenner and Formenti had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Brenner, Shuryak, DeWyngaert, Formenti.

Acquisition of data: Brenner, Jozsef, DeWyngaert, Formenti.

Analysis and interpretation of data: Brenner, Shuryak.

Drafting of the manuscript: Brenner, Shuryak.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Brenner, Shuryak.

Obtained funding: Brenner.

Administrative, technical, or material support: DeWyngaert, Formenti.

Study supervision: Formenti.

Conflict of Interest Disclosures: None reported.

Correction: This article was corrected for an error in the Results section on November 15, 2013.

References
1.
Little  MP, Azizova  TV, Bazyka  D,  et al.  Systematic review and meta-analysis of circulatory disease from exposure to low-level ionizing radiation and estimates of potential population mortality risks. Environ Health Perspect. 2012;120(11):1503-1511.
PubMedArticle
2.
Darby  SC, Ewertz  M, McGale  P,  et al.  Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987-998.
PubMedArticle
3.
Formenti  SC, DeWyngaert  JK, Jozsef  G, Goldberg  JD.  Prone vs supine positioning for breast cancer radiotherapy. JAMA. 2012;308(9):861-863.
PubMedArticle
4.
Ridker  PM, Buring  JE, Rifai  N, Cook  NR.  Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297(6):611-619.
PubMedArticle
5.
Chambless  LE, Heiss  G, Shahar  E, Earp  MJ, Toole  J.  Prediction of ischemic stroke risk in the Atherosclerosis Risk in Communities Study. Am J Epidemiol. 2004;160(3):259-269.
PubMedArticle
6.
Ng  J, Shuryak  I, Xu  Y, Clifford Chao  KS, Brenner  DJ, Burri  RJ.  Predicting the risk of secondary lung malignancies associated with whole-breast radiation therapy. Int J Radiat Oncol Biol Phys. 2012;83(4):1101-1106. Article
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